Significant improvements in the outcome of children with acute lymphoblastic leukemia have derived from the application of risk-adapted therapy. Age of the patient, laboratory features at diagnosis, biologic characteristics of the blasts, and early response to therapy, as measured both by conventional morphology and using technologies to detect minimal residual disease, all have been shown to affect outcome in ALL. In spite of improved outcomes, many patients who fail are those with good risk characteristics. Moreover, some patients are treated more intensively than they need to be may suffer from unnecessary toxicity. We hypothesize that the stratification of acute lymphoblastic leukemia can be improved by investigating the importance of different prognostic factors within homogeneously defined and treated subgroups of patients with ALL. To do this requires study of large numbers of patients;thus, we will carry out these studies in association with the phase III clinical trials of the Children's Oncology Group. In previous studies we have shown that we can use centralized reference laboratories to perform genetic stratification of patients in real time, and use the results to assign patients to treatment protocols based on genetic risk factors. We have also shown that in >95% of patients we can successfully measure minimal residual disease (MRD) in a timely fashion, and in so doing provide important prognostic information. The studies proposed in this grant will extend previous findings to different groups of patients and different time points, with the hope of further refining the ability to assign patients to optimal therapy. We plan to identify the relative contribution of genetic lesions, early marrow response, minimal residual disease, and NCI risk group classification to the overall prognosis of specific subsets of children with acute leukemia;to determine if we can combine favorable biological and response prognostic factors to identify patients who can be cured with minimal therapy;and to use minimal residual disease testing to identify additional patients who might benefit from therapeutic intensification, possibly including marrow transplantation. These studies will give us a better understanding of how to use prognostic information in treating children with ALL, and bring us closer to our goal of curing the maximum number of children with ALL with the least toxic therapy.